Hitherto, many aqueous drug compositions which are liquid at room temperature or lower and form a semi-solid or gel at body temperature of mammal have been disclosed for aqueous drug compositions which effectively release a pharmacologically effective component to mammal to be treated. U.S. Pat. No. 4,188,373 discloses aqueous drug compositions having property of thermosetting gelation, which comprise PLURONIC (trademark) and form gel by heating, and a desired sol-gel transition temperature thereof is obtained by controlling the concentration of PLURONIC. Moreover, U.S. Pat. Nos. 4,474,751, 4,474,752, 4,474,753 and 4,478,822 disclose drug delivery systems utilizing aqueous drug compositions having property of thermosetting gelation. The unique features of these systems are that both the sol-gel transition temperature and/or the rigidity of the gel can be modified by adjustment of the pH and/or the ionic strength and the polymer concentration. More recently, aqueous drug compositions, which form gel at a local region by changing pH and increasing temperature simultaneously (PCT WO 91/19481), are proposed.
However, the safety of the gelling materials used in these aqueous compositions is not necessarily certified with respect to all of the regions to be treated, and the high viscosity of the compositions in liquid state due to the high concentration of polymer in aqueous compositions results in the disadvantage that it cannot be easily used in a certain regions to be treated (for example, eyes). Japanese Patent Application Laid-open 62-181228 discloses a aqueous drug composition having property of sol-gel phase transition by ionic strength. This composition is characterized in that the concentration of the materials giving rise to a sol-gel phase transition is 10-100 times less than that of the aforesaid aqueous drug compositions having property of thermosetting gelation, and that it has no danger of gelation even if the surrounding temperature rises during storage, but it can be applied to only the specific region (for example, eyes).
On the other hand, it is well known that an aqueous solution of methylcellulose forms gel by heating and reverses to sol by cooling, in other words, its sol-gel phase transition is reversible, and researches on its mechanism have been considerably made.
OOba reports the relation of the degree of polymerization of methylcellulose and the concentration of methylcellulose to the gelling temperature, and the modification of gelling temperature by addition of ion, based on the experiment where an aqueous solution of methylcellulose is heated at a fixed rate to form gel (Hakodate technical specialized high school bulletin, No.22, 113-120, 1987). However, there is no description about aqueous compositions comprising methylcellulose which form gel at around body temperature of mammal.
Moreover, E. Heymann has determined the sol-gel transition temperature of an aqueous solution of methylcellulose with the content of methoxyl group of 35.4% (concentration of methylcellulose: 1.6%) when it is combined with salts. However, according to the experiment of the present inventors, when using methylcellulose (content of methoxyl group: 26-33%) as used in the present invention, the aqueous solution of methylcellulose with 0.2 mol of salt concentration (concentration of methylcellulose: 1.6%) has never formed gel at around body temperature of mammal.